3-Oxa(and thia) 11-deoxy PGE

ABSTRACT

This disclosure describes certain 11-hydroxy and 11-deoxy-9keto(or hydroxy)-prostanoic acid derivatives useful as bronchodilators, hypotensive agents, anti-ulcer agents, or as intermediates.

Elite iies r64 [1 [111 3, Bernady et al. Mar. 25, 1975 3-OXA(AND THIA) ll-DEOXY PGE 260/5()l.l7, 260/514 K, 260/586 11,424/305,

424/317 5 Invent Karel Franc Bemad 51 Int. Cl. C07C 149/26, C076 61/36 Brawner Floyd, Jr., both of Suffern, 58 Id fs h 760/468 D 514 D John Frank Poletto, Nanuet, all of 1 le 0 can N.Y,; Robert Eugene Schaub, Upper Saddle River; Martin Joseph Weiss, References C'ted Oradell, both of NJ. UNITED STATES PATENTS [73] Assignee: American Cyanamid Company, 3,773,795 11/1973 Bagli et a1 260/345.7

Stamford, Com OTHER PUBLICATIONS [22] Filed: Apr. 27, 1973 Karim et al., Prostaglandins, pp. 314-315 (1972).

21 A l. N .1355. 49 i 1 PP O 3 Primary Examiner-RObert Gerstl Related Application Data Attorney, Agent, or Firm-Edward A. Conroy, Jr. [63] Continuation-in-part of Ser. No. 274,768, July 24,

1972, abandoned. 57 ABSTRACT This disclosure describes certain ll-hydroxy and 11- de0xy-9-ket0(or hydr0xy)-pr0stan0ic acid derivatives 260/348 260/395 260M119 260(413 useful as bronchodilators, hypotensive agents, anti- 260/448 P, 260/4482 R, 260/448.8 R, 1 er 3 ts or asi ter ediat 260/456 R, 260/456 P, 260/468 D, 260/468 J, gen n m 260/468 K, 260/488 R, 260/501.1, 26 Claims, N0 Drawings [52] US. Cl 260/514 D, 260/240 R, 260/345.8,

1 2 3-OXA(AND T I IIA) ll-DEOXY FCE i having up to 3 carbon atoms; and the moiety C,. ,;C is ethylene, trans-vinylene, or cis-vinylene; CROSS REFERENCE To RELATED APPLICATION with the first proviso that when n is 1, R, is hydrogen, This application is a continuation-in-part of our R is hydrogen, Z is -(CH and C, C is pending appli ati n fi ly ethylene or trans-vinylene then R does not include a 1972 now abandoned. straight chain alkyl group having from 2 to 10 carbon BRIEF SUMMARY OF THE INVENTION atoms; and with the sectigiproviso that when Z is This invention relates to novel hydroxy substituted CH -CH=CH-(CH )p-,

prostanoic acids and derivatives as well as to intermedi- 10 ates and methods for their preparation. These methods embrace novel and useful procedures for the preparation of prostaglandin E l I-deoxyprostaglandin E l3-dihydroprostaglandin E and other known biologically important prostaglandin congeners. The novel compounds of this invention may be represented by the following general formula:

R is hydrogen, R is a straight chain alkyl group having from to 10 carbon atoms and R is hydrogen then C C 4- is ethylene or c is-vinyleiiei aridwith the third proviso that when R is alkyl then R, is hydrogen; and with the fourth proviso that only one unsaturated bond can be directly adjacent to C and with the fifth proviso that when R; is an alkyl group then the groups attached to the C position may have the 8a-alkyl(8- o iso) configuration of the formula: R

ll 0 Y -C a R 1 7 z 0 /Y I R3 c i Embraced within the scope of the present invention are all the possible optical isomers of the above general formula. Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R is hydroxy. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine wherein n is an integer having the value 1 or 2 ;R is hydrogen, lower alkoxy, triphenylmethyl, or triphenylmethyl in which one or two of the phenyl rings is substituted with an alkyl or an alkoxy group having up to 3 carbon atoms; R is a straight chain alkyl group having from 2 to 10 carbon atoms, a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with Cations Which as the "mower alkynamine cations alkyl groups each having from 1 to 3 Carbon (e.g., triethylamine, triethanolamine) procaine, and the atoms, a straight chain alkenyl group having from 3 to 10 carbon atoms and substituted with one or two alkyl The novel Compounds of the present invention are groups hm'lng bePWeen them from 2 5 Carbon atoms! usually obtainable as oils having characteristic absorp- 8 Straight Chill" y y group havmg from 3 to 10 .tion spectra. They are relatively insoluble in water but carbon atoms? 3 is y y of f allfoxy group'having are relatively soluble in common organic solvents such from 1 to l2 carbon atoms} 15 dlvalem radlcal as ethanol, ethyl acetate, dimethylformamide, and the lected from the group consisting of those of the formulike The Cationic Salts f h compounds When R3 is 21 droxy are, in general, white to yellow crystalline solids having characteristic melting points and absorption oaa Hon if spectra. They are relatively soluble in water, methanol, C or and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

Z is a divalent radical selected from the group consist 5O DETAILED DESCRIPTION OF THE INVENTION ing of those of the formulae: The prostaglandins are a family of closely related a. W cm. i4 A o R 5 wherein m is an integer from 3 to 8, inclusive, 1) is an compounds which have been obtained from various aneg from 2 t0 6 inclusive, 4 iS an alkyl group havimal tissues, and which stimulate smooth muscle, lower ng p to 3 Carbon moms. and R5 is n alkyl group havarterial blood pressure, antagonize epinephrine ing up to 3 carbon atoms, a fluorine atom, or a phenyl induced mobilization of free fatty acids, and have other group, 6 iS hydrogen or an alkyl grOup having up to pharmacological and autopharmacological effects in three carbon atoms; R is hydrogen or an alkyl group mammals. See Bergstrc'im et al., J. Biol. Chem. 238.

3 4 3555 (1963) and Horton. lzlrperienlia 21, l 13 (I965) wherein R' is an alkoxy group having from I to 12 carand references cited therein. All ofthe so called natural hon atoms; and n and Z are as hereinabove defined. prostaglandins are derivatives of prostanoic acid: The cycloalkenone intermediates may be readily pre- I CH CH2 CH2 coon c112 CH2/ cs CH CH CH CH 2 2 2 2 l CH2 CH2 \CHQ/ \CHE/ The hydrogen atoms attached to C-8 and C-l2 are in pared from Z-carbethoxycyclopentanone or trans-configuration. When the two side-chains (or the 2-carbethoxycyclohexanone in accordance with the re- C-8 and C-l2 hydrogens) are cis to each other, the action schemes set forth in Flowsheets A, B, C, l and compounds are referred to as 8-iso prostaglandins. The 15 J.

"FLows'HEET A CH n X-(CH2 )m COZCQHS O (II) (CH2) (C 2)n n (CH2 )m COECZHS co H (CH CO H 2 a 0 0 (III) (CH2) 40 0 11 2) 2 2 S 0 m o-fi-ca (VIII) natural prostaglandins represent only one of the possiwherein m and n are as hereinabove defined and X is hle optical isomers. The compounds of this invention iodo or bromo. In accordance with this reaction include all possible optical isomers. scheme. the cycloalk-Z-en-l-ones (VIII) are developed The novel compounds of the present invention may by first converting 2-carbethoxycyclopentanone or be readily prepared from certain cycloalkenone inter- 2carbethoxycyclohexanone (l) to the sodium enolates mediates which may be represented by the following thereof by means of sodium hydride in dimethoxyethgeneral formula: ane and then treating the sodium enolate with an ethyl (CH2 n m-haloalkanoate (II). There is thus obtained the corre- O sponding 2-carbethoxy-2-( w-carbethoxyalkyl )cycloalkanone (III) which is then hydrolyzed and decar- Z-C-R' boxylated to afford the 2-(w-carboxyalkyl)cycloalkanone (IV). This acid is then esterified with ethanol 0 whereby the 2-(w-carbethoxyalkyl)cycloalkanone (V) is obtained. The reaction conditions for carrying out the above sequence of reactions are well known in the art. The conversion of the cycloalkanone (V) to the enol acetate (VI) is effected by heating with acetic anhydride in the presence of p-toluenesulfonic acid. Preparation of the enol acetate (VI) usually requires heating for a period of from about 8 to 36 hours. During this period. it is preferable to allow by-product acetic acic to distill out in order to force the reaction to completion. The bromination of the enol acetates (VI) to the 2-bromocycloalkanones (VII) is preferably carried out in a two phase system as follows. A solution of bromine in chloroform is added to a rapidly stirred mixture of a solution of the enol acetate (VI) in chloroform and an aqueous solution of an acid acceptor such as calcium carbonate or soda ash. This addition is carried out at 05C. over a period of about half an hour, stirring is continued for an additional period of about half an 6 isolated by standard procedures well known in the art. Substitution Of X-(CH2),"C(R4)2CH2CO2C3H5 for (II) in Flowsheet A and carrying through the sequence of transformations illustrated therein is productive of the following cycloalk-2-en-I-one (VIIIa):

(on o R4 O R"I (VIIIa) 1 general structure (XVI), wherein the side-chain has a (cad -co c a lower alkyl group, fluorine atom or phenyl group alpha to the carbethoxy function, may be prepared in accordance with the following reaction scheme:

. FLOW-SHEET B Xen (cl-r I a. qwag -o-so -o a H a N oc'ns (x1) ocir, (XII) (c i 908MB (ca -o-so -a rm 45-3 K co cma (Kn) I (mm) vs =l I 2),, l 5 n l po c a (can -ca-co a (cag -e-a co t: a o oms 2 s hour to a few hours, and the product (VII) is then isolated by standard procedures. The dehydrobromination of the Z-bromocycloalkanones (VII) is preferably carried out in dimethylformamide with a mixture of lithium bromide and lithium carbonate at the reflux temperature for a period of about 30 minutes to an hour or so. The so formed cycloalk-2-en-I -ones (VIII) are also wherein n. m and R are as hereinabove defined and G is a lower alkyl or aryl group. In accordance with this reaction scheme, the 2-(w-carbethoxyalkyl)cycloalk-2- en-l-ones (IX) are converted to the corresponding I- methoximino-2-(w-carbethoxyalkyl)-2-cycloalkenes (X) by treatment with methoxyamine. With the ring carbonyl function thus blocked it is possible to effect a preferential reduction of the ester group by treatment with diisobutylaluminum hydride. The resulting alcohol (XI) is converted to a tosylate derivative (XII), which undergoes displacement on treatment with the sodium salt of a diethyl R -substituted malonate (XIII) to provide the disubstituted malonate derivatives (XIV). Hydrolysis and decarboxylation as well as concomittant cleavage of the methoximino blocking group provides the desired 2-(w-carboxy-w-R -substituted-alkyl)cycloalk-2-en-l-ones (XV), which are readily converted to the corresponding ester (XVI) by the usual procedure via the acid chloride and subsequent treatment with the appropriate alcohol in the presence of a tertiary amine.

The requisite Z-(w-carbethoxy-w-l-oxa-alkyl)cycloaIk-2-en-l-ones (XXII) and Z-(w-carbethoxy-w-lthia-alkyl)-cycloaIk-2-en-l-ones (XXVI) may be prepared in accordance with the reaction schemes of Flowsheet C, wherein n and m are as hereinbefore defined.

FLOWSHEET C (xvII) ocn,

"You, (xxzn) (ca: -S-CH -CO C H cohol (XIX) is converted on treatment with n-butyl lithium to the lithio alcoholate, which then is O alkylated by reaction with ethyl. bromoacetate to provide (XX). Hydrolysis with acetone-aqueous hydrochloric acid furnishes the deblocked keto-acid (XXI). which is then re-esterified with ethanol in the presence of p-toluenesulfonic acid to give the required Z-(wcarbethoxy-w-I-oxa-alkyl)cycIoalk-Z-enl-one (XXII). O-Alkylation can also be accomplished by treatment of the lithio alcoholate of (XIX) with sodium or other metal salt of bromoacetic acid, in which case the free carboxylic acid corresponding to ester (XX) is obtained. Hydrolysis as for (XX) provides the keto acid (XXI).

The preparation of the thia derivative (XXVI). proceeds from the intermediate alcohol (XIX), which after conversion to the tosylate intermediate (XXIII) and reaction with the sodium salt of ethyl mercaptoacetate furnishes intermediate (XXIV). Deblocking of XXIV with acetone-aqueous hydrochloric acid provides the (6: o (cu 40 021-1 (XVIII) o (xxvI) In accordance with the reaction scheme shown in Flowsheet C, for the preparation of the oxa derivative (XXII), an appropriate 2-( w-carbethoxyalkyl)cycloalk- 2-en-I-one (XVII) is converted to the corresponding methoxime (XVIII), the ester function ofwhich is then preferentially reduced with diisobutylaluminum hydride to afford the methoxime alcohol (XIX). The al- (tom) keto-acid (XXV). which on re-esterification with ethanol gives the required 2-(w-carbethoxy-w-l-thiaalkyl)cycIoaIk-2-en-I-ones (XXVI).

Certain of the l l-deoxy-9-keto(or hydroxy)- prostanoic acid derivatives ofthis invention, as defined in the general formula on page I above. may be pre pared from cycloalkenone (XXXI) and the triphenylmethoxy substituted l-alkyne (XXVlI) as depicted in Flowsheet D. In Flowsheet D, :1. R R';; and Z are as hereinabove defined; R' is a straight chain alkyl group having from 2 to l carbon atoms, a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with one or two alkyl groups each having from 1 to 3 carbon atoms, a straight chain alkenyl methyl group having from 2 to 9 carbon atoms, or a straight chain alkenyl methyl group having from 2 to 9 carbon atoms and substituted with one or two alkyl groups having between them 2 to carbon atoms; and R is a lower alkyl group.

FLOWSHEE'I' D the resulting alanate salt (XXX) to the cycloalk-Z-enl-one (XXXl) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also best carried out in an ether-type solvent such as diethyl ether, dubutyl ether, tetrahydrofuran, and the like. The intermediate alanate-enolate adduct is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXXII) are isolated in the usual manner well known in the art. Removal of the triphenylmethyl blocking group can then be accomplished by treating with weak acid. A preferred procedure involves heating at C. for 3.5

In accordance with the reaction scheme of Flowsheet D, the triphenylmethoxy substituted l-alkyne (XXVll) is treated with diisobutylaluminum hydride (XXVIll). This reaction of the l-alkyne (XXVll) with diisobutylaluminum hydride (XXVlll) provides the alane (XXIX) containing the trans-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 4060C. for several hours. It can also be carried out in a solvent such as tetrahydrofuran, usually in an approximate 2:1 mixture with benzene or hexane; in which case the reaction requires somewhat more vigorous conditions, usually treating at about 70-75C. for about 18 hours. The subsequent reaction with methyl or n-butyl lithium (R-Li) is preferably carried out in a mixture of the above solvents with an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran and the like. This reaction is rapid and is preferably carried out at OlOC. with cooling. The conjugate, l,4-addition of hours in a solvent system consisting of acetic acid:tet rahydrofuranzwater in the proportion of 4:2: l. Saponification in the usual manner of the resulting alkyl ester (XXXlll, R;,=alkoxy) provides the corresponding carboxylic acid (XXXlll, R;,=OH).

All available evidence leads us to the conclusion that in the product (XXXIll) the two side-chains attached to C and C are trans to each other. However, we are not certain of the configurational relationship in product (XXXII) as it is obtained directly from the alanatc process. These products may have the side-chains in a trans or cis relationship or they may be a mixture containing both the trans and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation of 81,. ln order to ensure a transrelationship in both (XXXll) and (XXXIll) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE to a mixture containing about percent of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

The triphenylmethyl blocking group for the hydroxy function in (XXVlI) etc. is an important feature of this process and other oxygen blocking groups, e.g., tetrahydropyranyl and alkyl, are not compatible with a clean cis-addition of diisobutyl aluminum hydride tuted with a lower alkoxy group, tetrahydropyranyl, a-(lower alkoxy) substituted lower alkyl, tbutyl, or a tri-(lower alkyl)silyl group; X is iodo or bromo; s is an integer having the value of one to three inclusive, and lis an integer having the value of one to three inclusive, with the proviso that the sum ofs and I must be equal to four.

(XXVllI) to the alkyne (XXVI!) to provide the desired trans-vinyl function.

Alternative procedures for the preparation of novel lithio alanute reagents useful for the introduction of the AMrans l5-oxy B-chain by conjugate l,4-addition are illustrated in Flowsheet K further below.

The intermediates for the introduction of the A"-l5- hydroxy side-chain are an integral part of this invention and they may be represented by the following general formulae (A), (B), (C), (D) and (E) wherein R is as hereinabove defined, R is a lower alkyl group, not necessarily the same for each use, and R is an alkyl group having from I to 10 carbon atoms not necessarily the same for each use, W is lower alkoxy, triphenylmethyl, or a triphenylmethyl group in which one or two of the phenyl rings is substituted with a lower alkoxy group; W is lower alkoxy, triphenylmethyl, a triphenylmethyl group in which one or two of the phenyl rings is substi- The alanate conjugate addition procedure is also useful for the synthesis of prostaglandin E (XL) as illustrated in Flowsheet E. This reaction sequence is carried out in the same manner as described for the sequence in Flowsheet D. It is to be noted that the introduction of the A -l5-oxy chain proceeds trans to the ll-oxy function. For this synthesis, it is best to use the tetrahydropyranyl or trialkylsilyl esters, since these esters can be hydrolyzed under conditions compatible with the stability of the B-ketol feature of prostaglandin E Alkyl esters would be hydrolyzed by fermentation with Bakers Yeast. The tetrahydropyranyl or trialkylsilyl, and triphenylmethoxy blocking groups are removed by mild acid treatment, for example with acetic acidztetrahydrofuranzwater (4:2:1) as described hereinabove. Application of the lithio alanate conjugate addition process to the synthesis of prostaglandins E and E is described below in connection with Flowsheet N.

13 FLOWSHEET E 14 groups, therefore, may be, for example, benzyl, diphenylmethyl, triphenylmethyl, tetrahydropyranyl, or a moiety of the formula:

CH e )s CH 5 3 H2)4 H3 )cwcsru-n a -C-CH -R cs (XXXIV) a 2 CH (xxxv wherein R is hydrogen, methyl or ethyl. Among the above-described blocking groups, we have found tertbutyl to be particularly convenient and useful. e i o sla (')C(C8H5)3 H CH cu cu H CH 0 \C=C 2l4 3 CH1 L1 \c=c/ H CH E H CHQTA H Flowsheet F CH2/ \CHECH CHS 2 CI: CH2CH(CH )z I ,4 3)2 .H(CH3)2 (XXXVI) (xxxvn) l Q t 1 2.0411 XMg-CH -CH -CHR O i 0 1 ll (XLI) (XLII) (CHQ)G E OO +Q(XXVII) Y O o (XXXVIII) O-Q 0 0 I l o CH -CH -CH-R (cn -rl-o (CH 2 2 2 Z-C-R' firtca pcit o H 0- 0(C5H5)3 (XXXIX) (XLIII) Jon h-coon a CHg-CHg-CH-Rg I h no tiH(CH CH H on 'E' it t, t The l3-dihydro derivatives (C13-C14 is ethylene) of this invention can be prepared by reduction of the A function in the corresponding l3-prostenoic acids of In accordance with the above reaction scheme, the

esters. This reduction can be accomplished by hydrogenation. However this procedure is not cleanly applicable in the presence of other double bonds in the molecule. In the latter instance the l3-dihydro derivatives are preparable via conjugate addition of a Grignard derivative (XLll) to cycloalkenone (XLl) in the presence of a catalyst such as the tributylphosphine-cuprous iodide complex as set forth in Flowsheet F, wherein 11, Z, R: and R';, are as hereinabove defined; Q is a blocking group; and X is chlorine, bromine or iodine, preferably bromine or iodine. The blocking group (O) for the hydroxyl function in (XLIl) can be any group stable to the Grignard reagent and which can later be removed by chemical treatment (e.g., mild hydrolysis or catalytic hydrogenolysis in the absence of carbon to carbon double bonds elsewhere in the molecule) to which the remainder of the molecule is stable. Suitable blocking conjugate 1,4-addition of a 3-(substituted hydroxy)alkyl or alkenyl magnesium halide (XLll) to a cycloalk- 2-enl-one (XLI) is carried out in the presence of a catalyst. In general, Grignard reactions with conjugated ketones provide 1,2-addition products; conjugate l,4- addition is usually accomplished when the reaction is carried out in the presence of a cuprous chloride or cuprous acetate catalyst. It is therefore most unexpected that the reaction of the cycloalkenone (XLI) with a Grignard reagent (XLll) in the presence of either of the aforementioned catalysts does not give appreciable amounts of the desired l,4-conjugatc addition PfUtl ucts. The novel feature of our process is provided by the use, as a catalyst, of a cuprous halide complex with a trisubstituted phosphine, a trialkyl phosphonate. a tertiary amine or a heterocycle containing a basic nitro gen (e.g., pyridine). We have found it preferable to use 15 tributylphosphine-cuprous iodide complex; (C,H,,);,P.Cul. The reaction is best carried out in the usual way in an ether-type solvent such as diethyl ether, dibutyl ether, tetrahytlrofuran, and the like. at room temperature for a period oftime of from 2 to 18 hours. 5 certainty. Therefore, the bond linking the Grignard- The intermediate magnesium halide-enolate adduct iS derived side-chain to the cycloalkyl ring is indicated by then hydrolyzed in situ. preferably With m um a bond in (XLIII). However, in any case. the subsechloride, at room temperature and the product (XLlll) quent deblocking and ester hydrolysis procedu is isolated on the usual manner well known in the art. sure the development, at least in predominant propor- When the blocking group is a tertiary alkyl moiety tion, of the thermodynamically favored transsuch as yl. deblOCking 0f t0 or relationship between the two side-chains,as is depicted (XLlV) is conveniently effected by treatment with glain structure (XLlV) 0f the reaction Schemecial trifluoroacetic acid at from 5 to l0C. for a pe- An alternative method for the introduCtion f t rind of l to 3 hours. Since this procedure may lead to A -l5-hydr y side-chain involves 1,4-conjugate addipartial trifluoroacetylation of the free hydroxy function to cycloalkenone (LV) ofa vinyl Grignard reagent tion, it is preferably followed by treatment with aque- [(Llll) (LlV)] in the presence of a catalyst such as ous ammonia (about 1.0N concentration) for about l5 the tributylphosphine cuprous iodide complex followed minutes at ambient temperatures. When the blocking by deblocking. From this process, in addition to the group is tetrahydropyranyl, is removal is readily efproduct (LVIII) containing the C -,C moiety as a feeted with dilute acid. When the blocking group is a trans-vinylene function there also is obtained the corremoiety such as benzyl, diphenylmethyl or triphenylsponding product (LIX) in which the C -C moiety methyl, deblocking of (XLlll) is convenientyl effected is a cis-vinylene function. These novel cis-A deriva-' by catalytic hydrogenolysis, procedures for which are tives are also embraced within the scope of this invenwell known in the art. In the instance of triphenyltion. The reaction sequence for the vinyl Grignard promethyl, deblocking is preferably effected by treating cess is illustrated in flowsheet G, which follows, and in with acetic acidztetrahydrofuramwater (4:221) at about which W n, Z, R and R are as hereinabove defined, 45C. for about 3.5 hours. and R is a straight chain alkyl group having from 2 Mild acid treatment results in hydrolysis of the tetrato 10 carbon atoms, or a straight chain alkyl group havhydropyranyl esters; alkyl esters can be hydrolyzed by ing from 2 to 10 carbon atoms and substituted with one the usual saponification techniques. or two alkyl groups having from 1 to 3 carbon atoms.

0 ll- R 2 H-CZC-H C-R' C=C I c1 u 01 (XLV) (XLVI) (XLVII) 0 H 8 ll ,C-R AlBr HCECH C-R i I Br H (XLIX) Br (XLVIII) (L) P 0-. H C-R"2 R C= /H c=c i a l l 8 Br H Br H (LI) (LII) When the cycloalkanone esters (XLIII) are formed by quenching ofthe reaction mixture with aqueous ammonium chloride solution, the relative stereo chemical relationship of the two side-chains is not known with ature of about C. After a period of about minutes to 3 hours the reaction mixture is poured onto aqueous concentrated ammonium chloride solution to give (LVI) (LVII). As explained hereinabove, at this stage the relationship of the two side-chains to each other is not determined. In any event, deblocking the IS-hydroxy function with weak acid (which procedure also hydrolyzes trialkylsilyl or tetrahydropyranyl esters) provides the product (LVIII) and (LIV) in which the chains are trans to each other. In the instance of alkyl esters, saponification provides the corresponding carboxylic acids. The A -cis and A -trans-isomers can be separated from each other by the usual techniques of chromatography; particularly useful is liquid-liquid partition chromatography.

The precursor 3-hydroxy-l-trans-alkenyl bromides (W alkoxy) I H trans 9- Z-C-R O n a 0 (LVIII) In accord withthe reaction sequence of Flowsheet G the vinyl Grignard reagent (LllI LIV), is prepared under an inert atmosphere in a relatively limited amount of anhydrous tetrahydrofuran. More vigorous conditions (e.g., heating in an oil bath at 70-8()C., one hour), for the formation of the Grignard reagent (LlIl LIV) favors the proportion of A -cis isomer (LIX) in the product of conjugate addition. Milder conditions (for example -47C., 1 hour) favors the proportion of A-trans isomer (LVIII) in the final product.

Conjugate addition of the vinyl Grignard reagent mixture [(LIII) (LIV)] to cycloalkenone (LV) is then preferably carried out by addition ofthe Grignard to the cycloalkenone dissolved in an ether type solvent, e.g.. diethylether, containing a catalyst such as the tributylphosphine-cuprous iodide complex at a temper- (LVII) (W alkoxy) (LI) can be prepared, as illustrated in Flowsheet G, by condensation of acetylene (XLV) with an acid chloride (XLVI) in the presence of aluminum trichloride. The resulting 3-oxo-l-chloro-trans-I-alkylene (XLVII) is then converted to the corresponding l-bromo derivative (XLVIII), by reaction with excess lithium bromide. This reaction is preferably carried out in ketone solvents, such as Z-pentanone or acetone. Reduction of the 3-keto function in (XLVIII), with for example, sodium borohydride provides the alcohol (Ll). The alcohol function is then blocked to give (LII). Alternatively, the 3-ox0 vinyl bromide (XLVIII) can be prepared directly from the acyl bromide (L) and acetylene (XLIX) in the presence of aluminum tribromide, preferably in ethylene dibromide.

The vinyl Grignard procedure outlined in Flowsheet G represents a novel, useful and convenient procedure 3,873,607 19 20 for the synthesis of l3-prostenoic acids and the novel below. Thus, in ofcyclopenteimnc (LX) with (irignzn'd Grignard reagents represented by formulae (Llll) and [(LXl LXll)]in accordance with the considerations (LIV) are to be considered as embraced within the discussed hereinabove, provides the conjugate addition scope of this invention. products (LXlll) plus (LXlV), mild acid hydrolysis of The vinyl Grignard technique can also be applied to 5 which furnishes prostaglandin E (LXV) and A-cis a useful synthesis of prostaglandin E and the novel prostaglandin E, (LXVl), separable by chromatogra A""-cis-prostaglandin-E as illustrated in Flowsheet H, phy.

FLOWSHEET I-l 0 (cHQ -g-o-LD O H o \0 l 1 als a Q (LxIII) mm 0 C; O \Q\ ',I\/\(CHE)4CHS o 2 32 H H O 6 'fi I (Clhkfi-O- o 0 I o o (LXIII) v (LXIV) (W alkoxy) (W alkoxy) Flowsheet H continued trans H OH OH HO )YKWHQNHS H0 i /K (CH -COOH The preparation of the cycloalke'none intermediates (LXXVI, LXXVII) bearing a cis double bond in the carboxylic acid side chain can be accomplished by the FLOWSHEET I (CH2)8COOH (LXVI) sequence illustrated in Flowshcet I, which follows and in which n and p are as hereinubove defined.

c0 0 zCHz-OCH (LXVII) (LXVIII) (cs cu cu ocn Q 2 2 a 0 m n o a lizocn o (LXIX) (m) Br Q!) O CH CH OCli CHZCHZOCHS (LXXV) (LXXVII) In the above Flowsheet l, the sequence wherein a 2-carbalkoxycycloalkanone (LXVlI) is transformed to a Z-(fl-hydroxyethyl)cycloalk-2-en-l-one (LXXlll) is carried out in a manner described in Flowsheet A. Methyl ether cleavage of the corresponding Z-(B- methoxymethyl)cycloalkenone is achieved by treating with boron tribromide. Oxidation of the alcohol (LXXlll) with Collins reagent [chromium trioxidepyridine complex in methylene chloride under anhydrous conditions; J. C. Collins, W. W. Hess, and F. J. Frank, Tetrahedron Letters. 3363 (l968)l Provides the aldehyde (LXXlV), which is then treated in anhydrous dimethylsulfoxide with the ylid (LXXV) preparedfrom an (w-carboxyalkyl)-triphenyl phosphonium bromide and sodium hydride. The use of dimethylsulfoxide as a solvent for this reaction leads to the predominant formation of the desired cis double bond derivative (LXXVI). The acid function in (LXXVI) can be esterified in the usual fashion; with diazomethane, the methyl ester (LXXVll) is obtained.

Cyclopentenones such as (LXXVI wherein n=1 may also be prepared by the sequence illustrated in Flowsheet 1, which follows and in which p is as hereinabove defined.

FLOWSHEE'I J (LXXIX) (LXXVIII) H H cis cH -'t :="c-(cH coon p WHO \2 (cna-c=c-(ca cooa (LXXXI) H cis (CH2-C;'C'(CH2) coon (LXXXII) In Flowsheet J above the bicyclic hemiacetal (LXXVllI) [P.A. Grieco, Journ. Org. C/HHL, 37, 2363 (I972)] is treated with ylid (LXXlX) to give the l-hydroxy-3-cyclopentene (LXXX). Oxidation with Jones reagent gives the corresponding ketone (LXXXI), which on base treatment furnishes the required cyclopentenone (LXXXll), which can then be esterified in the usual manner.

Certain of the intermediates illustrated in Flowsheets l and J. in particular the compounds of formulae 24 (LXXI), (LXXlI), (LXXlll), (LXXlV), (LXXVI) (LXXVll) (and related esters), (LXXX) and (LXXXl) are novel and useful compounds and are embraced within the scope of this invention.

Alternative procedures for the preparation of the alanate intermediates to that discussed in connection with Flowsheet D above are illustrated below in Flowsheet K, wherein R, R' R" and W are hereinabove defined.

FLOWSHEET K 0 0 ll ll H ,C-R" G H C-R" c=c I c=cf 01 a 7 I a (LXXXIII) (LXXXIV) \l/Na-BH4 0W OH Ease "2 H\ )C R'2 /C\ c=c c=c a I H I H (LXXXV) (LXXXVI) (W ?W H C-R' H C-R' R' Al Li a H a a) R' A1-R' Li I 1 (LXXXVII) (LXXXVIII) AlCl f R'AlCl R 2 C\ In H C=C\ H 9 H l I R R Li ow I (LXXXIX) H 9 R a H 3 5 R' -C H 2 I I b C-R' 2 H C=C =C l H Al I a G) H 6B R Li 25 In accordance with the sequence of Flowsheet K above the l-iodo-trans-l-alkenyl-3-oxo derivative (LXXXlV) is prepared by iodide interchange, preferably in acetone or similar ketone, from the corresponding chloride (LXXXIII), the preparation of which is described in connection with Flowsheet G above. Reduction of (LXXXIV) to the alcohol (LXXXVI) can be accomplished in the usual manner with sodium borohydride. The hydroxy function is then blocked to give (LXXXV, R' R" Treatment of the acetylene,

r HC =C-CH-R' with one equivalent of disiamylborane (prepared in situ from diborane and 2-methyl-2-butene) and then with excess anhydrous trimethylamine oxide followed by treatment with an aqueous solution of excess sodium hydroxide and a tetrahydrofuran solution of excess iodine is also productive of (LXXXV). Treatment of the trans-l-alkenyl iodide (LXXXV) at low temperatures, preferably at about 30 to 78C., in an inert solvent, e.g.', hexane or toluene, with an alkyl lithium, e.g., butyl lithium, provides the trans-l-alkenyl lithium reagent (LXXXVll). Treatment of this lithio derivative with a tri-alkyl aluminum furnishes the trans-l-alkenyl trialkyl alanate (LXXXVIll). Treatment of a dialkyl aluminum chloride with two molar equivalents of lithio reagent (LXXXVII) gives the bis(trans-l-alkenyl)dialkyl alanate (LXXXIX) and treatment of an alkylaluminum dichloride with three molar equivalents of lithio reagent (LXXXVIl) affords the tris(trans-l-alkenyl) alanate (XC).

Each of the three types of alanates, (LXXXVlIl), (LXXXIX) and (XC), can be utilized for 1,4-conjugate addition reactions as described hereinabove in connection with Flowsheets D and E above. Thus, substitution of (LXXXVllI), (LXXXIX) or (XC) for alanate (XXX) in Flowsheet D will provide the indicated products of the Flowsheet. Similarly, substitution of (LXXXVIll), (LXXXIX) or (XC) in which R, is npentyl for alanate (XXXVll) in Flowsheet E provides prostaglandins E. In general the mono alkenyl alanate (LXXXVIII) is preferred because it is more economical in the use of vinyl halide.

With regard to the cycloakenones of Flowsheets D, E, F, G and H it should be noted that the blocking groups for the 4-hydroxy functions as well as for the carboxylic acid may also be a tri-alkylsilyl group, e.g., trimethylsilyl, dimethyl-t-butylsilyl or dimethylisopropylsilyl. Cyclopentenones blocked in this manner are illustrated below in formula (XCl) and (XCll) wherein m, n, Z and R (not necessarily the same for each use) are as hereinabove defined.

(xcn) All the novel products of this invention exclusive of certain intermediates bear a hydroxy or oxy function substituted at or at what ultimately becomes the atom of the product prostanoie acids and esters. Thus in at least most instances a l5-norma|" and a l5-epi racemate is obtained in at least near equal proportions. Each of the racemates contains equal amounts of the enantiomer wherein C is in the S configuration and the enantiomer wherein it is in the R configuration. The racemates are separable from each other by the usual techniques of chromatography. Also, resolution in the usual way of the B-chain precursor [for example, the resolution of 3-hydroxy-l-octyne is described in the literature [see R. Pappo, P. Collins and C. Jung. Ann. N. l. Ac'ad. ofSeience, I (Prostaglandins), 64( 1971); J. Fried et al., ibid, p. 381 1. Resolution prior to the conjuguate addition operation will provide the diasterom ers wherein the C atom is either in the 15(5) or 15(R) configuration, as desired. Separation of the diastereomers so obtained, for example, by chromatography, will give the fully resolved (d and 1) products provided there are no asymmetric carbon atoms other than at C and C The presence of other asymmetric sites re quires additional resolution steps in order to obtain a single atipode. The compounds of this invention embrace all possible optical isomers.

The ll-deoxy-9-keto derivatives (XClV) of this invention can be converted to the corresponding 9- hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 901 and 9B-hydroxy derivatives (XCIll) and (XCV) as set forth in the following reaction scheme:

FLOWSHEET L (xcv) wherein R R R R Z, n and C,;,-C are as hereinabove defined. In general, when the reaction is carried out with lithium perhydro-9B-borophenalyl hydride {H. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc., 92, 709 (1970)] the product is at least pre dominantly the )a-hydroxy derivative (XClll), wherein the 9-hydroxy group is cis to the sidechain attached to C 27 ln accordance with accepted convention, an a-substituent at the 8-. 9-. or l2-positions is behind the plane of the paper whereas a B-substituent at these positions is in front of the plane of the paper. This is usu- 28 C to give the lS-ketone (XCVlll). Blocking of the re maining hydroxy function as a trimethylsilyl ether gives (lC) which is reacted with the alkyl Grignard, R Mgl. to give the l5-alkyl-l5-hydroxy derivative (Cl). Hydroally represented by a bo d f an b i m a 5 lysis of the silyl ether blocking group then gives the diol fl-'b0nd for a B-substituent, and ambo d wh ester (C), saponification of which gives (Cll). Oxidaboth are indicated. Thus. the 9-hydroxy derivatives lion 0f the Secondary g'hydroxy function in P may b variously represenmd as f H vides the l5-alkyl-9-oxo ester (Clll), saponification of which furnishes (ClV). (A similar sequence can be efl0 fected with the A-cis-series.)

C C c The processes of this invention are also useful for the W a preparation of prostaglandin E and prostaglandin E H OH H OH H OH and thus also PGF a and PGF -,a by reduction, for example with lithium perhydro-9B-boraphenalyl hydride. A useful procedure for the introduction of the l5- 15 The 4-hydroxycyclopentenone intermediate (CXI) relower alkyl group (R is illustrated by the sequences quired for these syntheses is prepared in accordance of Flowsheet M. which follows. with the procedure illustrated in Flowsheet N which FLOWSHEET M z-co c as (XCVI) (XCVII) o (CH2) ARE \RT z-co c a (xcvI'II) z-coon (CII) (CIV) (CIII) follows and in which is also shown the transformation of this compound to prostaglandins l5: and E In Flowsheet N. J is an appropriate blocking group for the hydroxy and ester function in (CXl) which is compatible with the conjugate addition reaction and also is ulti- 29 30 mntely removable by acid-catalyzed hydrolysis or other pose are the tetrahydropyranyl group and various techniques which will not disrupt the sensitive I l-oxytrialkylsilyl groups (e.g., dimethylisopropylsilyl, tri- Q-keto system in the products (CXlll), (CXV), methylsilyl, dimethyl-t-butylsilyl and the like. ((XVlll) and (CXVll). Particularly useful for this pur- FLOW SHEET N (CV) (CVI) c on (CVIII) cooit no on (CIX) coon OOH 0H no (car) (an) o /C\O2H W i (CXIa) (club) 31 32 FLOWSHEET N Continued in accordance with the above reaction scheme the 3,4-epoxylactol (CV) [E. .1. Corey and R. Noyori, Tetrahedron Letters, 311 (1970)] is treated with the ylide (CV1) to give the 3,4-epoxycyclopentanol (CVll) bearing the a-chain of the prostaglandin 2 series. Oxidation (for example with H CrO .H SO -ether or Jones reagent) of (CV11) provides the epoxy ketone (CVlll). mild base treatment of which results in the initial formation of the 4-hydroxycyclopent-2-en-l-one (CXl) and the isomeric 3'hydroxycyclopent-4-en-l-one (CX) as a mixture. Further treatment of this mixture with dilute base under mild conditions (preferably pH 10.3-10.6 for 24 hours) results in the isomerization of the 3-hydroxy isomer (CX) to the desired (CXI). We believe that the transformation of the epoxy ketone (CVlll) to the hydroxyeyclopentenones (CX) and (CXl) and the isomerization of (CX) to (CXl) may take place through the intermediacy of the 3.4-diol (ClX It is also conceivable that isomerization of (CX) to (CXI) proeedes via the epoxy derivative (CVlll) or the corresponding a-epoxide (CXlb); it is further eon eeivable that (CVlll) procedes to (CX) and (CXI) directly without the intermediacy of (ClX). Another possible intermediate for the isomerization of (CX) t (CXI) is the corresponding diene (CXla). The preparation of (CXI) is also possible via the a-epoxide series from (CXlc) via the a-epoxide corresponding to (CVIl) and (CVIII) such as (CXlb) or via a mixture of the a and B epoxides. In practice, it is most convenient to utilize a mixture of aand ,B-epoxides (CXlc and CV). The hydroxy and acid function in the 4- hydroxycyclopentenones (CXI) are then appropriately blocked to give (CXII). Appropriate blocking groups are tetrahydropyranyl, trimethylsilyl, dimethylisopropylsilyl. dimethyl-t-butylsilyl and the like. Treatment of (CXll) with the lithio alanate (CXIV) or its equivalent (see the discussion hereinabove for Flowsheets K and E) gives the conjugate addition product (CXllI) in which the configuration at C is undetermined. Mild acid treatment, for example with acetic acid: tetrahydrofuranzwater, (412:1), of (CXllI) results in the removal of blocking groups, and if necessary equilibration to all all-trans configuration, to give prostaglandin E (CXV). Similarly treatment of (CXll) with the lithio alanate (CXVI) gives prostaglandin E (CXVII).

Substitution in Flowsheet N, of ylide (CXIX), wherein p is as hereinabove defined, for the ylide (CV1) provides, by transformations analogous to those described in Flowsheet N [(CV) to (CXI) and (CX1l)]. the 4-hydroxycyclopent-2-en-l-ones (CXX) and their blocked ether-esters (CXXl). These novel and useful intermediates are a part of the present invention.

i CH2 19 (max) 0 (CH2 c0011 H 2.2. 1-! H0 (cxx) (ca C-O-J H 22?; H J0 The 8B-lower alkyl group (R' is introduced as illustrated in Flowsheet 0 below via the bromomagnesium enolate (CXXV). This novel and useful intermediate is obtained by conjugate addition of the l-alkenyl (irignard reagent [(CXXlll) (CXXIVH. preferably prepared at about 35C.. to the eycloalkenonc (CXXll) in the presence of a catalyst such as the tri-nbutylphosphine cuprous iodide complex as described hereinabove in connection with Flowsheets G and H. It is also possible to utilize for these purposes in an analo gous manner the magnesio enolate (CXXVlll) obtained by conjugate addition of Grignard (XLll) to cycloalkenone (XLl) as described hereinabove in connection with Flowsheet F, in which case the 13.14- dihydro derivative of this invention are obtained. in Flowsheet 0 below, :1. Z. R;,. R R- W R O and X are as hereinabove defined and R is an alkyl group having up to 3 carbon atoms. When the magnesio enolatc (CXXV) is treated with a lower alkyl halide. e.g., methyl iodide. it undergoes alkylation at the XB-site providing. after dcblocking of the lS-oxy group in intermediate (CXXVl), the 8B-alkyl derivative (CXXVll). ln the instance of alkyl esters. saponification gives the corresponding carboxylic acids (CXXVll, R;,=OH). The compounds corresponding to (CXXVll) wherein C -,C is a cis-vinylene double bond are preferably prepared by utilizing the vinyl Grignard reagent prepared at temperatures in the range of 7()75C., as discussed hereinabove (Flowsheets G and H).

Also obtained from the alkylation of (CXXV) is the 8a-alkyl-8-iso derivative corresponding to (CXXVl). which after deblocking provides the 8a-alkyl-8-isoproducts (CXXIX). Usually the Set-product is formed to a significantly lesser extent than the 8B-product (CXXVI). The 8a and 8,8 products are separable from each other by the usual techniques ofchromatography.

FLOWSHEET O Continued (cxxvI) (W2 i alkoxy) (cxxvIII) (CXXIX) Application of the 8-alkylation process to the l l-oxy series provides the novel compounds of, formula (CXXX), wherein R R R Y and C ,C are as hereinabove defined and wherein R is an alkyl group having up to 3 carbon atoms, R,, is selected from the group consisting of hydrogen, lower alkanoyl, tetrahydropyranyl and tri-lowcr alkylsilyl groups, R is selected from the group consisting of hydroxy, alkoxy having from 1 to 12 carbon atoms, tetrahydropyranyloxy and tri-lower alkyl silyloxy groups, Z is a divalent radical selected from the group consisting of those of the formulae:

H cis H CH -O-CH and -CH -C CI C wherein m p, R, and R are as hcreinabove defined; and the moiety with the proviso that only one unsaturated bond can be directly adjacent to C,;,; and with the second proviso that when R is alkyl then R, is hydrogen; and with the third proviso that the groups attached to C may be in the SB-alkyl (8-iso) configuration:

The novel compounds of formula (CXXX) are also embraced by this invention. The preparation of these compounds may be illustrated by the reaction sequence ofFlowsheet P below, wherein R Z W R- R; and R are as hereinabove defined and R has all the possibilities defined above for R except that it is not hydrogen.

[(CXXIII) (cxxxv)] FLOWSHEET P Continued (cxxxnz) (cxxxv) In accordance with the sequence of Flowsheet P above, treatment of the ether-ester 4- oxyeyclopentenone (CXXXl) with the l-alkylene Grignard reagents [(CXXlll) (CXXlV)] (see Flow sheet 0) gives the bromomagnesio enolate (CXXXll). This operation also results in the introduction of the trans C -C double bond (as shown in CXXXll), as well as the corresponding compound with the cisdouble bond. The trans bond is favored when the Grignard is prepared at lower temperatures, about C.; the cis-bond at higher temperatures, about 7()75C. This point is more fully discussed above in connection with Flowsheets G and H. The magnesio enolate (CXXXll) is a key intermediate and when it is treated with a lower alkyl halide, e.g. methyliodide, it undergoes alkylation to give the 8,8-lower alkyl derivative (CXXXlll). Deblocking of the IS-hydroxy blocking group (e.g.. triphenylmethyl), and of the llhydroxy tetrahydropyranyl or trialkylsilyl ether blocking groups as well as of the tetrahydropyranyl or trialkyl silyl esters is accomplished under mild acid conditions, e.g. heating at C. for 3.5 hours in a solvent system consisting of acetic acid:tetrahydrofuran:water (4:2:1 This procedure provides (CXXXV). The particularly of structure (CXXXV) or (CXXXlIl) can be converted to 8,8-alkyl prostaglandins of the A class (CXXXIV) by treatment with acid or base, a preferred procedure involves treatment in tetrahydrofuran:water (2:1) solvent ().5N in hydrochloric acid for about 70 hours at ambient temperatures.

The novel compounds of this invention represented by formula (CXXXlV) and related compounds are particuularly interesting sunce they represent stabilized prostaglandin A types. which cannot rearrange to the biologically relatively inactive prostaglandins of the B series.

Utilization of Grignard (XLll) (see Flowsheet F, hereinabove) in the sequence of Flowsheet P provides the compounds of (CXXX) wherein C,;,C is ethyl ene. Provided there are no other double bonds in the molecule these substances can also be obtained by catalytic hydrogenation of the compounds represented by formula (CXXXV).

The alkylation process described above for Flowshects O and P also gives the corresponding 8a-alkyl oxy) derivatives which are separable from the 8B-alkyl isomer by chromatography. Thus, for example, in Flowsheet 0 treatment of enolate (CXXV) with R l gives not only the 8B-alkyl product (CXXVl) as shown, but there also is obtained the 8a-alkyl derivative (CXXXVI) shown below. In Flowsheet P, alkylation of enolate (CXXXll) also provides, in addition to (CXXXlll) shown, the 8a-alkyl-8-iso product (CXXXVll), shown below. These 8oz-alkyl-8-iso derivatives can be deblocked and carried through the same series of transformation shown for the SB-derivatives (CXXVl) and (CXXXlll) in Flowsheets O and P, respectively. These novel 8a-alkyl-8-iso derivatives and their transformation products are also a part of this invention, are the key intermediate enolates represented by structures (CXXV) and (CXXXll).

The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer 

1. THE RACEMATE OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE REPRESENTED BY THE STRUCTURAL FORMULA:
 2. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is
 3. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is
 4. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 5. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 6. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 7. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 8. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 9. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 10. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 11. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 12. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is
 13. The racemate according to claim 1 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is
 14. A compound selected from the group consisting of those represented by the structural formula:
 15. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is
 16. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pEntyl, Y is
 17. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 18. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 19. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 20. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 21. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 22. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is 1,1-dimethyl-n-pentyl, Y is
 23. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 24. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is thia, R3 is hydroxy, R2 is n-pentyl, Y is
 25. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is
 26. The compound according to claim 14 wherein n is 1, R7 is hydrogen, m is 4, X is oxa, R3 is hydroxy, R2 is n-pentyl, Y is 